CD39 May Impact Clopidrogrel Pharmacodynamics?

Short Communication

Austin J Clin Immunol. 2014;1(1): 1005.

CD39 May Impact Clopidrogrel Pharmacodynamics

Joanna Lecka1,2, Michel Fausther1,2, Mireia Martín-Satué1,2,3 and Jean Sévigny1,2*

1Département de microbiologie-infectiologie et d’immunologie, Faculté de Médecine, Université Laval, Québec, QC, Canada.

2Département of immunologie,Centre de recherche du CHU de Québec, Québec, QC, Canada.

3Departament Patologiai Terapèutica Experimental, Facultat de Medicina, Universitat de Barcelona-Institut d’InvestigaticióBiomèdica de Bellvitge, Barcelona, Spain

*Corresponding author: Jean Sévigny, Centre de recherche du CHU de Québec, 2705, Boulevard Laurier, local T1-49, Québec, QC, G1V 4G2, Canada

Received: January 09, 2014; Accepted: January 14 , 2014; Published: January 17, 2014


NTPDase1; clopidogrel; pro-drug; thrombosis; PON1; P2Y12

Thrombosis is treated with antithrombotic drugs such as clopidogrel. Clopidogrel which is widely prescribed after heart attacks is a pro-drug that must be metabolically activated to the form that irreversibly blocks platelet P2Y12 receptors. Bouman et al. [1] lately showed that the esterase paraoxonase-1 (PON1) was an enzyme involved in the catabolism of clopidogrel. Importantly, they showed that a common PON1gene polymorphismentails variability inclopidogrel’s clinical efficacy, a factor thought to be a major drawback to its use. This implies that PON1 genotyping might identify subjects unlikely to benefit from clopidogrel treatment. In agreement, E.Dolgin [2] described a case history of clopidogrel resistance correlating with low PON1 activity in a patient harbouring this genetic variant [3,4]. Taubert et al. [4] demonstrated that the P2Y12 antagonist is generated by the action of 2 enzymatic steps performed by cytochrome P450 (CYP2C19) and by PON1. They also showed that the latter is the ratelimiting step responsible for clopidogrel resistance. This explanation was confirmed by Homes MV et al. [5] in an extensive study, on over 42,000 patients, where no clinically significant interaction of CYP2C19 genotype with the association of clopidogrel therapy and cardiovascular events was shown.

The prognosis of patients on clopidogrel therapy that possess poor PON1 activity [1] might in fact be worse than expected. Indeed, Lecka et al. demonstrated that clopidogrel inhibits NTPDase1 activity [6]. NTPDase1 is responsible for ADP clearance from the blood and protects from uncontrolled platelet aggregation [7]. Indeed ADP is an important agonist of platelet activation and aggregation that is the natural ligand of P2Y12 and also of P2Y1, both expressed on platelets and responsible for their aggregation [7,8]. An oral dose of 30 mg clopidogrel, which constitutes 5% of the actual recommended therapeutic dosage, is expected to peak in the blood at ~20 μM. At this concentration, clopidogrel inhibited NTPDase1 activity, with either ATP or ADP as a substrate (>60% inhibition of ADPase activity). As a result, such inhibition favoured platelet aggregation in vitro [6]. These data are in agreement with the increased thrombosis and fibrin deposition found in cd39+/- mice in which the total enzyme activity of NTPDase1 (aka CD39) is reduced by half [7,9]. Conditions that diminish NTPDase1 activity have also been correlated with increased thrombosis and inflammation in several models [9-11].

Therefore, the previous comment suggesting that clopidogrel and its intermediary metabolites are “inactive” [12], on the assumption that they are not antagonists of P2Y12 receptors, may reveal to be wrong. The study by Leckaet al. [6] rather suggests that in the absence of the active metabolite of clopidogrel, the “P2Y12 inactive” clopidogrel pro-drug might in fact favour thrombosis by decreasing NTPDase1 activity [Figure 1]. This effect, which might be increased and/or prolonged in patients where the catabolism of clopidogrel to its active form is impaired, such as in subjects with low PON1 and/or CYP2C19 activity [2-4,12], would be expected to precede the therapeutic action of clopidogrel (i.e. dependent on drug metabolism). In agreement with this observation [6], we show here that 100 μM clopidogrel blocks the hydrolysis of ATP by endothelial NTPDase1 at the surface of both human umbilical vein endothelial cells (HUVEC) and also at the surface of blood vessels in liver and pancreas tissues ([Figure 2] and data not shown).

Citation: Lecka J, Fausther M, Martín-Satué M, Sévigny J. CD39 May Impact ClopidrogrelPharmacodynamics. Austin J Clin Immunol. 2014;1(1): 1005. ISSN : 2381-9138